Studies during the last year were focussed in these area: a) Plasma catecholamine responses in humans following intravenous administration of an alpha2 antagonist, idazoxan, have been characterized and shown to be highly correlated, not with the density of platelet alpha2 receptors but the shape of the epinephrine mediated inhibition of forskolin stimulated cyclic-AMP. This provides the first evidence in humans that an integrated physiologic response which as norepinephrine release to an alpha2 antagonist may be predicted on the basis of the functional state of alpha2 receptors on platelets. Application to populations with affective illness in which alpha2 function may be abnormal is underway. b) Since idazoxan binds to non-alpha2 so-called imidazoline sites, there is a possibility that some of its effects do not reflect antagonism of alpha2 receptors. Under our direction a Phase I study of a truly selective analogue that does not bind to other sites, ethoxy idazoxan, has been successfully completed in the United Kingdom. Based on this data, we are in the process of obtaining an IND to administer to humans in this country. c)We obtained and administered U-78875, a compound with mixed benzodiazepine agonist/antagonist activity to 10 healthy volunteers in an attempt to separate sedative from neuroendocrine effects and model pharmacodynamic response vs drug concentration. Data analyses are still underway.